Introduction

    It is widely recognized that panic disorder is one of the most common and potentially debilitating illnesses encountered in psychiatry. Patients with panic disorder experience considerable morbidity, suffer from psychosocial disruption, and are at risk for alcohol and substance abuse. The severity of the illness has led to an tremendous amount of research into its  etiology and treatment over the past two decades.

   The core clinical feature of panic disorder is the spontaneous panic attack, a rapid crescendo of intense anxiety associated with numerous somatic symptoms such as palpitations, dyspnea, tremor and chest pain. In addition, psychological symptoms such as fears of going crazy, of losing control and of dying are prominent. The experience of panic is exceptionally frightening; patients often believe they are having a heart attack, stroke or another medical emergency.

     Spontaneous panic attacks by definition occur out of the blue, without any environmental or psychological trigger. The unpredictability and severity of the panic phenomenon leads patients to develop fear of experiencing subsequent attacks once one has occurred. This fear is known as anticipatory anxiety. In an effort to counter this anxiety, patients often avoid situations where a panic attack has occurred, such as in a subway, over a bridge, or other places where escape may be difficult. Unfortunately, this avoidance behavior can then generalize to several other situations and may render the patient housebound, unable to venture out unless accompanied by a trusted companion. This severe form of avoidance is known as agoraphobia, occurring in approximately 30% of patients as a significant complication of the illness.

     This chapter will focus on the pharmacological therapy for panic disorder.  All major classes of effective agents will be reviewed.  A section on experimental drugs is included, demonstrating that the search for effective drugs is no longer entirely dependent on serendipity, but instead  can be directly yielded by advances in neurobiological science. The complicated and chronic course of panic disorder leaves several sufferers refractory to treatment; an approach to the treatment resistant patient is therefore presented in closing.

 

Tricyclic Antidepressants

     In 1964, Donald Klein ushered in a new era of psychopharmacology when he discovered  the powerful antipanic properties of the tricyclic antidepressant  imipramine, leading to his intitial identification of the panic disorder syndrome.  Soon thereafter Klein confirmed this original finding in a randomized, double-blind placebo controlled study of thirteen patients (1) . Imipramine was able to block spontaneous panic attacks with subsequent  reduction in overall disability. Following this landmark observation, widespread deployment of TCAs ensued; before the introduction of SSRIs  these medications, together with the high potency benzodiazepines,  represented the standard pharamacological therapy for panic disorder. Imipramine remains the most intensively studied tricyclic for panic and numerous controlled trials (2- 8) have since definitively documented its therapeutic efficacy and superiority to placebo on measures of  panic, agoraphobia and anticipatory anxiety.  The pattern of response has been noted as follows. First, after approximately two to four weeks and continuing into the eighth to twelfth weeks of treatment, patients experience a reduction in both frequency and severity of panic attacks. Second, blockade of spontaneous panic leads to attenuation of patient’s anxiety regarding the occurrence or consequences of future attacks.   Third, the experience of decreased anxiety diminishes the reinforcing potential of  any agoraphobic behaviors. Doses of imipramine employed in these studies ranged from 35mg/day to 300mg/day.     

      Positive results have also been demonstrated with clomipramine, a strongly serotonergic tricyclic antidepressant. Unfortunately, enthusiasm has been  tempered by clomipramine’s strong  propensity to cause adverse effects in panic patients.  An eight week, placebo controlled trial (9) of female agoraphobics demonstrated superiority of clomipramine over placebo at a mean dose of 83 mg/day. However, this study also reported a 58% dropout rate secondary to medication intolerance.   A 12 week double blind, placebo controlled study (10) found clomipramine, at an average dose of 109mg/day,  actually superior to imipramine at endpoint  in both reduction of panic attacks and attenuation of general anxiety.  It should be cautioned, though, that the average imipramine dose employed was 124mg/day, which may have been subtherapeutic. Subsequently, an open  trial (11) showed clomipramine (128mg/day) to be at least equal in efficacy to imipramine (144mg/day). Our group at Columbia (12) entered 58 panic patients in a 13 week clomipramine study and found 84% of completers to be markedly or moderately improved. In addition, doses of less than 100mg/day of clomipramine were able to exert antipanic effects.  However, a 45% dropout rate occurred due to adverse events, with most of these patients having dropped out in the first two weeks. In view of the above studies, it is interesting that a recent study by Broocks et al (13) comparing the effects of aerobic exercise, clomipramine and placebo for forty six  panic disorder patients found not only that clomipramine was the superior treatment, but also that clomipramine group had a 0% dropout rate, despite a comparatively high average dose of 112.5mg/day.   

    Few other tricyclics have been systematically evaluated for the treatment of panic.  A 6 week open trial of desipramine (14) found it ineffective in blocking panic, but able to confer protection against phobic anxiety. Similarly, Lydiard et al (15) found in a 12 week placebo controlled study that desipramine did not differ significantly from placebo in the  ability to reduce panic attacks at endpoint. Phobic avoidance and Hamilton anxiety ratings, however, were effectively reduced by desipramine as compared with placebo. Nortriptyline was found to be effective in an open trial (16); further evidence of nortriptyline’s antipanic potency has rested on anecdotal clinical reports. The only reported study with maprotline (17) found it to have less antipanic efficacy than fluvoxamine in a double blind comparator study.            

     The adverse and complicated side effect profile of TCAs is the major factor limiting the feasibility of this class for the treatment of panic.  Anticholinergic, antihistaminergic and antiadrenergic effects are quite common. In addition, fatigue, cognitive impairment, weight gain and sexual dysfunction are problematic and are factors affecting patient compliance. The potential for cardiac dysrhythmias and orthostatic hypotension warrant extra caution when prescribing to  elderly patients and those with systemic illness.  Fatality in overdose is another disadvantage that may preclude use of these medications in potentially suicidal patients.

       Moreover, panic disorder patients are exquisitely sensitive to the early stimulating effects of TCAs, and  commonly experience anxiety, agitation and insomnia upon initiation of treatment (18). To offset this initial supersensitivity, it is prudent to begin with a  comparatively low dose (10mg/day or its equivalent) of imipramine. After introducing the medication at a low dose, it can be gradually titrated upwards by approximately 10 mg every 2-3 days,  with careful attention to the emergence of any stimulant like effects.

     It is as yet unclear what the optimal target dose of tricyclic antidepressants for panic should be. To specifically address this question, Mavissakalian and Perel (19) randomly assigned patients to low dose (35mg/day), medium dose (99mg/day) or high dose (200mg/day) and found  medium and high dose, but not  low dose , superior to placebo. Further, an earlier study by the same group demonstrated a superior response with imipramine doses of greater than 150 mg/day, whereas doses of 130mg/day or less were not distinguishable from placebo(20) .  A reasonable strategy may therefore begin with an inital dose of 10mg/day, titrating upwards to 100mg/day, then allowing for an adequate time to respond (eg. 4-6 weeks). If response is inadequate, a gradual increase to 300mg/day would be warranted(21). With respect to clomipramine, the above studies suggest that it can exert antipanic effects  at somewhat lower doses than imipramine, ranging from 50-150mg/day. 

       Once the target dose of a particular TCA  is established and deemed effective, the duration of treatment beyond the acute phase (usually 8-12 weeks of therapy) needs to be determined. This has unfortunately been a relatively neglected area in the literature. However, an emerging series of studies has significantly improved our understanding of the salient issues regarding the long term antidepressant treatment of panic disorder.

       Mavissakalian and Perel (22 ) assigned panic patients to receive either 6 months of acute treatment with imipramine followed by discontinuation, or 6 months of acute treatment followed by 1 year of maintenance therapy with imipramine at half-dose. Discontinuation of imipramine involved a steady taper over 3 months. Results showed that 75% of patients who had responded to the 6 month treatment phase (at an average imipramine dose of 168.4 mg/day) relapsed within 6 months following discontinuation of the medication. In contrast, patients who received the a dditional 1year of maintenance treatment of 85.8mg/day did not show any evidence of relapse during this time.  A follow up study by the same investigators (23) attempted to determine the 6-month relapse rate of patients beyond the maintenance phase. 14 panic patients who completed the total eighteen months  of acute (full dose) plus maintenance (half dose) phases were compared with 16 patients who completed only the 6 month acute treatment. Results clearly demonstrated a protective effect of maintenance therapy, as evidenced by a much lower relapse rate of 25%.  Further, Curtis et al (24) continued imipramine, alprazolam, or placebo in 181 patients for 8 months following 8 weeks of successful acute treatment and demonstrated significant improvements with imipramine and alprazolam as compared with placebo. There was no need for dose escalation in either medication group. The investigators suggested that the effects of imipramine were somewhat longer lasting than alprazolam’s.  Taken together, these studies suggest that maintenance therapy needs to be a critical consideration in the pharmacotherapy of panic. Specifically,  treatment for at least one year after an acute phase is likely to be advantageous in long term therapy. Severely ill individuals with a more chronic course of symptoms and increased likelihood of relapse may require an even longer maintenance period of two years or greater.  Further research is also required to determine the exact dose necessary to maintain remission over the long term.

 

Selective Serotonin Reuptake Inhibitors

     The introduction of SSRIs into clinical practice heralded a revolution in the pharmacotherapy of psychiatric disorders. The superior side effect profile and comparable efficacy to older medications have established this class as first line treatments for several diseases, including panic disorder. The prodigious use of these agents for the treatment of panic disorder emerged from a confluence of two factors: first, the increased recognition of the neurobiological role for serotonin in the pathophysiology of anxiety and second, the demonstrated usefulness of these medications in several controlled studies and clinical trials.

     Fluoxetine was the first SSRI shown to exert an antipanic effect. Gorman et al (25), in an open trial, showed significant improvement in panic symptomatology in a small group of patients. This study had a high (50%) dropout rate secondary to SSRI induced jitteriness.  Schneir et al (26) reported that 76% of patients were markedly improved at the endpoint of an open label study, with a much lower dropout rate than Gorman et al’s study. Fluoxetine was compared with desipramine in a small, double blind study(27); although endpoint scores demonstrated greater improvement with fluoxetine, there was no statistical significance between the two groups. A multicenter, randomized, double blind study (28) compared two  doses of fluoxetine (10 and 20mg/day) and placebo. Results showed that fluoxetine 20mg/day was superior to placebo on most measures studied, including the Clinical Global Impressions Scale (CGI). In contrast, the 10 mg dose was not different from placebo, suggesting superior efficacy of fluoxetine at higher doses.

     Sertraline has also been the focus of considerable research.  Gorman and Wolkow (29) reported on pooled data from two large, multicenter, doubleblind placebo controlled studies of sertraline in the treatment of panic disorder. Three hundred twenty patients were evaluated over 12 weeks. Patients were assigned to 50, 100, and 200mg fixed doses of sertraline versus placebo.  Results demonstrated that all doses of sertraline reduced the frequency of panic attacks versus placebo at the 12 week endpoint.  Duboff et al (30) found that in one of the above multicenter studies,  sertraline treatment at all doses significantly reduced anticipatory anxiety compared with placebo. Wolkow et al (31) studied 176 panic disorder patients in a multicenter, 10 week, double blind, placebo controlled trial. They utilized an initial titration step of 25 mg for the first week, followed by 50 mg at end of week 1. From the end of the second week onward, doses were titrated flexibly from 50 to 200 mg/day. At the 10 week endpoint, patients in the sertraline group had significantly fewer panic attacks than the placebo treated patients, and were more improved on a global evaluation scale.  The employment of titration reduced treatment discontinuation due to side effects to a nonsignificant difference with placebo as compared to utilization of a fixed dose.

     Double blind, placebo controlled trials of paroxetine have firmly established its place in the antipanic pharmacologic armamentarium. Steiner et al (32) first demonstrated dose response with 40 mg of paroxetine being far superior to placebo. However, 10 and 20mg fixed dose groups were ineffective. Ballenger et al also demonstrated the efficacy of 40 mg of paroxetine in treating panic, suggesting that a minimun of 40 mg is necessary for therapeutic effect.  In addition to demonstrating paroxetine’s antipanic efficacy for an acute treatment period, Burnham et al (33) also showed that treatment for an additonal 3 months with paroxetine resulted in a 5% relapse rate, as compared with a 30% relapse rate with placebo.  Oehrberg et al (34) carried out a placebo controlled study with both groups (paroxetine and placebo)  receiving cognitive behavioral therapy. Paroxetine was superior to placebo on two of three outcome measures. Clinical response was maximized with use of higher doses, such as 40 to 60 mg/day. A multicenter, double blind, placebo controlled study by Lecrubier et al (35) comparing paroxetine with clomipramine showed that paroxetine and clomipramine were equivalent in efficacy, and paroxetine was clearly superior to placebo. Paroxetine was also found to have more rapid onset of action than clomipramine, as measured by the treatment time required to reduce the number of panic attacks to zero. Paroxetine was better tolerated than clomipramine, with adverse experiences reported similar to placebo. An option of continuing treatment for an additional 36 weeks after the 12 week acute treatment period was offered to patients, and 176 patients entered this extension study. Improvement in the number of panic attacks was reported in all three groups; however, paroxetine continued to demonstrate superior effects during this phase compared to placebo, with paroxetine treated patients demonstrating significantly fewer full panic attacks compared to baseline and being more likely to be panic free at the completion of the study.  The clomipramine group also demonstrated continued improvement and at the endpoint there were no significant differences between paroxetine and clomipramine. Although fewer paroxetine treated patients withdrew from treatment compared with clomipramine treated patients, this difference was not statistically significant (36).                 

   Studies with fluvoxamine have conclusively demonstrated its superiority to placebo in antipanic efficacy.  Black et al (37) investigated the efficacy of fluvoxamine versus CBT versus placebo in a randomized trial of 75 outpatients. Results demonstrated that fluvoxamine was superior to both cognitive therapy and placebo. However, it is important to note that the relatively low response to cognitive therapy (40%) may have been due to the use of week 4 as the comparison time point, which was possibly not long enough to allow for the full benefit of CBT to occur.  Sharp et al (38) , studying 190 panic patients, compared fluvoxamine alone, fluvoxamine in combination with CBT, and  CBT alone. No statistical difference was found between treatment with fluvoxamine alone versus fluvoxamine plus CBT versus placebo plus CBT. All three of these treatments were superior to CBT alone; CBT alone was superior to placebo alone. Studies without placebo control which have compared fluvoxamine to other medications have demonstrated superiority to maprotiline (17), equivalent efficacy to clomipramine (39), and equivalent efficacy to brofaromine (40). Studies with placebo control with comparison trials have shown fluvoxamine to be superior to ritanserin(41)  and equal to imipramine (42).  A double blind, placebo controlled comparison study by Nair et al (43) reported negative results with fluvoxamine. However, these results may have been confounded by a lower frequency of panic attacks at baseline for the placebo group, a shorter (by 2 weeks) treatment period for the fluvoxamine group, and benzodiazepine discontinuation in the fourth week of treatment in the fluvoxamine group, exacerbating anxiety and withdrawal symptoms.

     The side effect profile of SSRIs involves headaches, irritability, nausea, sexual dysfunction and insomnia. The lack of action at cholinergic, histaminergic and adrenergic receptors make these agents very tolerable for all patients. In particular, the elderly are likely to benefit from the SSRIs’ decreased ablilty to exacerbate underlying medical conditions, especially cardiovascular disease. The favorable side effect profile universally ensures improved compliance with medications prescribed. Another major advantage of these medications is their safety in overdose; even with the presence of life threatening suicidal ideation, these agents may still be employed.

        One of the most critical aspects of SSRI therapy is initiation of the medication at a low dose to prevent or lessen SSRI induced anxiety, agitation and tremor, also known as the jitteriness syndrome. This cluster of symptoms is unfortunately very common in panic patients and an untimely experience of the syndrome may lead to noncompliance and reluctance to accept further attempts with pharmacotherapy.  An appropriate starting dose for fluoxetine would be between 5- 15mg/day, with titration to 40-60mg/day. The lowest dose effective for paroxetine in published studies has been 40 mg/day, and a reasonable starting dose would be 10mg/day.  Sertraline’s  effectiveness has been documented equally at 50, 100 and 200mg/day doses.  Sertraline can be initiated at 25 mg/day with gradual titration up to the above doses.  Fluvoxamine should be started at 50mg/day and increased to a target of 150mg/day (21).

      Compared with the literature on imipramine, there is a relative paucity of data on what constitutes an optimal length of treatment with an SSRI.  As the above studies suggest, medication discontinuance shortly after the acute treament period is associated with greater relapse than that seen with maintenance therapy beyond the acute phase.  Continuation of treatment over 6-12 months is an effective way to sustain the antipanic effects of an SSRI.  Discontinuation of treatment after an extended trial  needs to be performed gradually to prevent the emergence of withdrawal symptoms such as anxiety, tremor and insomnia.

 

Benzodiazepines

     Although antidepressants are the mainstay of treatment for panic disorder, benzodiazepines are also widely used. The main indications for benzodiazepines in panic disorder are 1. severe illness necessitating rapid amelioration of panic 2. the initiation phase of  antidepressant treatment when therapeutic effect is not yet achieved and there is risk of stimulant effects 3. as an adjunct medication for patients partially responsive to antidepressants and  4. for patients unable to tolerate the side effects of antidepressants.

     The most extensively studied benzodiazepine for the treatment of panic has been the high potency triazolobenzodiazepine  alprazolam.  The Cross National Collaborative Panic Study (CNCPS) (44), a multicentre study conducted in two phases, is generally regarded as the most ambitious attempt to demonstrate the antipanic efficacy of alprazolam. Phase One of the CNCPS (45) randomly assigned 481 panic disorder patients (80% of whom had agoraphobia) to alprazolam or placebo, utilizing a double blind design and flexible dose schedule.  All groups received their respective treatments for 8 weeks.  Treatment was then discontinued over 4 weeks, and subjects were followed for 2 weeks after discontinuance.  The mean dose of alprazolam employed was 5.7mg/day. Alprazolam was shown to have a rapid onset of effect, with most improvement occurring in the first week of treatment.  Alprazolam was far superior to placebo on measures of panic attacks, anticipatory anxiety and phobic avoidance; at the 8 week endpoint, 55% of alprazolam treated patients were panic free, compared to 32% of those given placebo.

     Phase two of the Cross National Collaborative Panic Study (46) attempted  to not only replicate phase one’s results in a larger sample, but also to compare alprazolam’s efficacy to that of a typical antidepressant treatment for panic.  1168 panic patients were randomly assigned to alprazolam, imipramine, or placebo for 8 weeks.  This follow up study confirmed the earlier findings demonstrating  superior antipanic activity of alprazolam (mean= 5.7mg/day) and imipramine   (mean=155mg/day) compared with placebo, with 70% of both imipramine and alprazolam groups experiencing amelioration of panic compared to 50% for placebo. Significant drug effects were demonstrated for anticipatory anxiety and phobia. As in the phase 1 study, most of alprazolam’s beneficial effects were witnessed in the first and second weeks; imipramine, however, took four weeks or more to exert antipanic action.  The main criticism of the Cross-National Study, forwarded by Marks et al (47), was that the high level (approximately 30%)  of placebo dropouts due to inefficient treatment may have confounded the analysis of the endpoint data.

      In addition to the CNCPS, several trials have conclusively established alprazolam’s efficacy in the acute and long term treatment of panic (48-52,21). Almost all studies found alprazolam to be superior to placebo in treating phobic avoidance,  reducing anticipatory anxiety, and lessening overall disability.  Further, comparator studies of  alprazolam and imipramine found the two medications comparable in efficacy for panic attacks, phobias, Hamilton anxiety, CGI and disability. These studies have additionally revealed alprazolam to be uniformly better tolerated than imipramine, with a quicker onset of therapeutic effect. 

      Another high potency benzodiazepine shown to be effective for panic is clonazepam. Two studies are particularly relevant.  Rosenbaum et al (53), in a double blind placebo controlled study of 413 panic patients, found that daily doses of 1.0 mg or greater (patients were randomly assigned to 0.5, 1.0, 2.0, 3.0 or 4.0mg doses) were superior to placebo in reducing the frequency of panic attacks.   This study entailed a gradual upward titration of dose over a 3 week period, maintenance at a fixed dose for 6 weeks, and then a gradual discontinuation over 7 weeks. Interestingly, although the discontinuation phase caused worsening of most patients’ symptoms, no patient reverted to their baseline or preclonazepam functioning. This may indicate a sustained therapeutic effect of  clonazepam even after a maintenance treatment period is completed. Tesar et al (54), in a 6 week placebo controlled trial comparing clonazepam and alprazolam, also found that clonazepam (mean=2.5mg/day) and alprazolam (mean=5.3mg/day) , as compared to placebo, significantly reduced panic attacks and improved global functioning; no differences on anticipatory anxiety were observed. 50% of the clonazepam group, 46% of the alprazolam group, and 14% of the placebo group were panic free for two consecutive weeks. Clearly, clonazepam is a reasonable alternative to alprazolam.  The advantages of clonazepam therapy are  primarily due to its long half life, allowing for less frequent dosing and decreased probability of interdose rebound symptoms.  

       Lorazepam has also been shown to be equivalent to alprazolam in antipanic efficacy. A 6 week, double blind trial of 241 panic patients (55) comparing lorazepam (mean= 7mg/day) and alprazolam(mean=3mg/day) showed comparable efficacy in reducing panic attacks for both medications. Charney and Woods (56) demonstrated equivalent antipanic action for both alprazolam and lorazepam in 48 panic patients treated over 6 weeks.

        Despite the widely held view that low potency benzodiazepines are relatively weak antipanic agents, controlled studies have demonstrated that low potency drugs are comparable in efficacy to their high potency counterparts. In a double blind, placebo controlled study over an 8 week treatment period (57), diazepam (43mg/day mean) and alprazolam (4.9mg/day) were both found to be superior to placebo, as well as equal in efficacy and tolerability.  Dunner et al (58) found that random assignment of 48 panic patients to 10 weeks of diazepam, alprazolam or placebo resulted in significantly superior reductions in panic frequency in the treatment groups.  These studies challenge the notion that high potency benzodiazepines are uniquely specific for panic.

      The side effect profile of benzodiazepines involves mainly sedation, fatigue, ataxia, slurred speech, memory impairment, and weakness. It is important to be mindful of the potential for cognitive impairment when prescribing to the elderly. Further, the risk of falls in elderly secondary to incoordination and fatigue is increased.  Sustained benzodiazepine treatment may also promote the occurrence of dysphoria and depression.

      The major concern with benzodiazepine treatment is the likelihood of physiological dependence. Longstanding clinical observations and several experimental studies have now documented the emergence of a hazardous withdrawal syndrome upon discontinuation of these medications.  Rickels et al (59) demonstrated that after an acute treatment phase of 8 weeks and a subsequent maintenance phase of 6 months with alprazolam (mean=5.7mg/day) , 63% of patients experienced significant withdrawal symptoms and recurrence of panic attacks during a 4 week taper phase.  In addition, 33% of subjects were unable to discontinue medication.  Fyer et al (60) demonstrated severe withdrawal symptoms during gradual alprazolam discontinuation  in 50% of patients studied, with panic attack recurrence in 14 of 15 patients identified as panic free. Noyes et al (61), in a study comparing diazepam with alprazolam, showed that discontinuation of either medication resulted in withdrawal symptoms. However, patients discontinued from alprazolam experienced a more severe withdrawal syndrome, highlighting the fact that discontinuance effects are more marked with short half life (eg. alprazolam) as compared with longer half life (eg. clonazepam) agents. The severity of withdrawal is also a function of dosage used and length of treatment. Rickels et al demonstrated that patients unable to taper alprazolam were receiving on average a higher dose. It is of further importance to recognize that withdrawal and reemergence of symptoms can occur after even a relatively brief period of benzodiazepine treatment (eg. 6-8 weeks), necessitating slow taper for any patient prescribed these medications.

     Reticence to prescribe benzodiazepines among clinicians has been based on the unwarranted asssumption that patients will develop tolerance to the anxiolytic effects and steadily increase the effective dose, similar to a pattern of abuse seen with users of illicit substances. Studies have shown, however, that panic patients without premorbid or comorbid alcohol and substance abuse conditions are no more likely to abuse benzodiazepines than the general population . In addition, patients with panic (as well as other anxiety disorders) experience an escalation of dose beyond therapeutic requirement as unpleasant and associated with unwanted somatic effects(62,63).  

     Two studies have directly compared the efficacy of different doses of  alprazolam. Uhlenuth et al (64) assigned 81 panic patients to 2mg of alprazolam, 6mg of alprazolam, 225 mg of imipramine , or placebo for 8 weeks.  They showed that patients that recieved alprazolam at 6mg/day were less symptomatic than patients receiving 2mg/day.  In contrast,  Lydiard et al (65), in a 6 week, double blind, fixed dose study found minimal differences between patients treated with low (2mg) dose (50% response) compared with high (6mg) dose (65% response), although there was a 23% incidence of surreptitious benzodiazepine use with the lower dose group. Doses of 6mg resulted in a greater incidence of side effects and consequently an increased dropout rate. It is conceivable that more significant differences between low and high dose  could have emerged if fewer of the high dose group left the study.  Clinical consensus suggests an average maintenance dose of 2-4mg/day in divided doses of alprazolam. Higher doses of up to 10mg/day may be necessary for severely ill patients, but at these doses the risk for adverse effects is substantially increased.  Clonazepam’s longer half life allows for less frequent (1-2x/day) dosing than alprazolam.  Rosenbaum et al’s multicenter trial  of clonazepam employing a range of doses (.5-4mg/day) found a minimum effective dose of 1 mg/day , with a range between 1-2mg/day suggested as optimal treatment (21).

     Although studies such as the CNCPS have established alprazolam’s efficacy in the acute phase, long term treatment studies on benzodiazepines are lacking. However, follow up of patients enrolled in clinical trials has shed light on this issue. Pollack et al (66) followed patients who entered a placebo controlled study of alprazolam and clonazepam.  Approximately 80% of the patients were still taking medication 18 months after the trial, and 40% of these patients were continuing to experience panic symptoms.  Worthington et al (67) naturalistically followed 204 patients, 45% of whom were taking clonazepam, over a two year period. Results showed that clonazepam maintained its therapeutic effect at two years without an escalation in dose.  In a follow up to the phase I CNCPS, Du pont et al (68) prospectively monitored 142 subjects who continued alprazolam after the 8 week acute phase, and found that 53% of patients were still taking alprazolam at follow up.  These studies underscore the necessity for long term benzodiazepine treatment  to maintain therapeutic antipanic effects.

      Studies comparing the long term efficacy of benzodiazepines with antidepressants have produced conflicting results. Rickels et al (69) found that class of medication (ie. alprazolam or imipramine) did not predict whether a medication would be required at two year follow up. In contrast, a 3 year follow up of 55 panic patients treated with alprazolam or imipramine for 9 weeks (70) showed that twenty-nine (54%) patients were still using their initial medication at follow up. Moreover, twenty of these twenty-nine patients requiring continued medication were from the alprazolam group, whereas only nine were from the imipramine group.  More research is clearly  warranted to determine if long term treatment with benzodiazepines can exert the same beneficial effects as  that of antidepressants.

 

Monoamine Oxidase Inhibitors

     Extensive use of MAOIs is no longer commonplace in the pharmacological management of most psychiatric disorders. The clinical reality of serious side effects and strict dietary requirements has relegated these agents to at best second or third line status. However, evidence does exist for therapeutic potential of MAOIs in panic. An early placebo controlled study by Sheehan et al (71) examining 57 patients with phobic neurosis over 12 weeks demonstrated that both phenelzine (45mg/day) and imipramine (150mg/day) were superior to placebo. Unfortunately, panic attacks were not monitored, and the study was conducted at time when the phenomenology of panic was not rigorously defined.  Interestingly, phenelzine was observed to be better tolerated than imipramine.  An open trial of phenelzine (mean=55mg) (72) showed that 97% of patients who completed a 6 month treatment period were panic free and experienced reductions in anticipatory anxiety.

     The introduction of reversible inhibitors of MAO-A (RIMAs) initially seemed promising; the tyramine free diet obligatory with older MAOIs is not a factor at therapeutic doses. Further, the antipanic potential of the RIMA brofaromine  has been demonstrated in an 8 week , double blind trial comparing brofaromine and clomipramine (73). A multicentre, double blind study (74) comparing moclobemide (450mg/day) and fluoxetine (20mg/day) over 8 weeks found comparable efficacy for the two medications. Unfortunately, few other studies have been carried out, and medications such as brofaromine and moclobemide are currently unavailable in the U.S.

     The major risk of MAOI therapy is hypertensive crisis following ingestion of tyramine.  A strict low tyramine diet is mandated for all patients. Medications such as sympathomimetic amines, decongestants, dextromethorphan, and meperidine must be avoided. A severe serotonergic syndrome may be precipitated if MAOIs are used concurrently with SSRIs.  Other adverse effects include weight gain, hypotension, sexual dysfunction and insomnia.

      The effective dose of phenelzine is approximately 45mg/day. Some clinicians have suggested that higher doses (eg. 90mg/day) may be necessary to treat panic. No literature currently exists regarding an optimal maintenance dose of MAOIs or length of treatment. Given the multiple risks of treatment, MAOIs should be reserved for patients refractory to the other treatments available.

 

Nefazodone

     Nefazodone is a newer agent that combines inhibition of the reuptake of 5-HT with antagonist activity at the 5-HT IA receptor. Its efficacy in major depressive disorder is somewhat lower than the SSRIs but its side effect profile is more favorable, making  it increasingly appealing to psychopharmacologists. Studies on nefazodone in panic are limited but show promise. A randomized placebo controlled trial was retrospectively analyzed to compare the effects of nefazodone and imipramine in patients with comorbid anxiety and depressive disorder.  The nefazodone treated patients demonstrated a significantly greater reduction in panic symptoms compared with imipramine (75). In addition, 71% of panic patients treated with nefazodone in an open label trial experienced reduction in panic symptomatology (76). Nefazodone treatment should be reserved as an alternative after treatment with the major anti panic medications has been attempted.

 

Venlafaxine

    Venlafaxine is a structurally novel antidepressant which inhibits reuptake of both norepinephrine and serotonin at the synaptic level, combining the theorized mechanisms of action of both cyclic antidepressants and the SSRIs. Venlafaxine maintains a more favorable side effect profile than the cyclic antidepressants, secondary to little or no affinity for muscarinic, histaminergic or adrenergic receptors.  Although established as an efficacious antidepressant, it is slowly emerging as an alternative to existing therapies for panic disorder. Pollack et al (77) demonstrated venlafaxine’s antipanic potential in a double blind, placebo controlled trial of 25 panic patients.  A clinical study of panic disorder and venlafaxine (78) reported complete elimination of panic attacks with administration of low doses (50-75mg/day) of venlafaxine, albeit with only a small number of patients (N=4).  Papp et al (79) found that venlafaxine at low doses (mean,46.9mg) completely eliminated panic attacks in all(N=13)  patients in an open trial. Common to all studies was a general pattern of early treatment emergent side effects, specifically nausea, headache, jitteriness and insomnia. Given the small sample sizes, extrapolation from these studies is limited but should stimulate further inquiry into the use of this medication for the treatment of panic disorder.

 

Calcium Channel Blockers

     It has been hypothesized that certain physical symptoms of the spontaneous panic attack, such as palpitations, tachycardia, dizziness and paresthesias, are manifestations of underlying cardiovascular and cerebrovascular pathophysiology. An early double blind study by Klein and Uhde (79) found that verapamil, a calcium channel blocker widely utilized in the treatment of heart disease, had significant antianxiety and antipanic effects compared with placebo. Although no other controlled trials have been carried out, an open trial (80) reported moderate success with diltiazem in the treatment of panic. An interesting study by  Gibbs (81) measured basilar artery blood flow via doppler in panic patients and normal controls and found that the panickers demonstrated a much greater decrease in blood flow following hyperventilation compared to normals. Further, two subjects with significant blood flow decrease were successfully treated with nimodipine. The results of this study tentatively suggest that calcium channel blockers  may exert their therapeutic effects through  stabilization of  a hyperresponsive vasculature in panic disorder.  Although not likely to become first line agents, calcium channel blockers may be useful in refractory cases as well as certain subtypes of panic that display increased somatic symtomatology.  The utility of calcium channel blockers in panic is an uncertain and needs further investigation.

 

Experimental Drugs

Corticotropin releasing factor

     A vast preclinical literature now exists which provides compelling evidence for the role of corticotropin releasing factor (CRF) in the genesis and regulation of anxiety and stress related behaviors. Crucial to the appreciation of the function of CRF in anxiety has been the localization of several CRF- expressing  neurons and CRF- receptors within the amygdala . The amygdala and its inherent connections, both afferent and efferent,  are currently understood to be the central areas of a distinct neuroanatomical substrate putatively coordinating several major aspects of the anxiety response in animals.

     Functional analyses of CRF action have consistently demonstrated that direct application of CRF into the amygdala has anxiogenic effects. CRF injections diminish exploratory activity, increase freezing behaviors and enhance the acoustic startle response (83).  A novel CRF related peptide, urocortin, increased anxiety expression of rodents during several behavioral challenges (84). Laboratory induction of immobilization stress produces measurable increases in CRF levels (85).

     Conversely, CRF antagonists have been shown to exert a potent anxiolytic effect. Administration of alpha helical CRF 9-41, a specific CRF antagonist, produced a marked attenuation of freezing behavior in several studies(86) .  CRF 9-41 was shown to prevent the anxiogenic effect of neuropeptide Y antagonist in the elevated plus maze test (87).  Saryani et al (88) demonstrated that administration of  CRF antiserum could reduce anxiety secondary to cocaine withdrawl in rodents. CRF involvement in anxiety also extends to interactions with the serotonin and norepinephrine systems. CRF 9-41 could reduce the sound-stress induced increase in tryptophan hydroxylase(89).  With respect to  norepinephrine, CRF 9-41 infusion into the locus ceruleus decreased immobilization stress induced defensive withdrawl (90). Considering the power of these agents to control anxiety and their interrelationship with neurotransmitters definitively implicated in anxiety pathophysiology, extrapolation from the area of CRF antagonist development may have important implications for the therapeutics of anxiety diseases in humans, particularly panic disorder.

Substance P

     Recent years have witnessed an increased interest in the neurokinin substance P and its relevance to the pathophysiology of anxiety.  Preclinical studies have demonstrated that intrapertioneal administration of high (500 ug/kg) doses of substance P result in an anxiogenic-like effect (90).  In a recent clinical study, Weiss et al (91) examined 22 male volunteers in Jerusalem during and after  the Iraqi missile attack on Israel in 1991, and performed a series of neuroendocrine assays. All subjects demonstrated increased anxiety during the attacks. Most interestingly, however,  was the finding of elevated levels of substance P (as well as ACTH and neurotensin) during the period of heightened anxiety.

     If substance P is associated with the anxiety response in humans and across species, it is plausible that an antagonist of substance P would prove to be anxiolytic. File (92) administered CGP 49823, a substance P antagonist at neurokinin 1 receptors, and demonstrated a clear anxiolytic  effect on a social interaction paradigm.  The most striking finding of this study  was that diazepam administration also produced an anxiolytic effect; however, after 3 weeks of diazepam treatment, tolerance developed to the anxiolysis and there emerged a clear anxiogenic withdrawal  response. In contrast, there were no anxiogenic withdrawl effects observed with CGP 49823 and the anxiolytic action was sustained.  Extending preclinical work on substance P to the clinical front, Kramer et al (93) , in a placebo controlled trial, demonstrated that the substance P antagonist MK 869 was an effective antidepressant agent. Unfortunately, MK869 has not been developed further based on later data that was not promising. The therapeutic potential of substance P is a nascent area requiring more research.

 

Measurement of Clinical Outcomes

     Clinical trials of pharmacotherapy for panic disorder need to be scrutinized with respect to the specific outcome measures utilized to determine efficacy.  One method commonly employed is a determination of the actual frequency of spontaneous panic attacks. This can be accomplished by patients recording the occurrence of panic attacks in a panic attack diary.  Although very useful for evaluating frequency, the panic attack diary does not address the severity of individual panic attacks. Overall disability and severity of illness are often measured with the Clinical Global Impressions (CGI) Scale.  The CGI, however, is limited in its ability to as sess core symptoms of panic and the ratings are subject to significant   interpreter bias. Furthermore,  psychometric validity of the CGI and other global measures such as the Brief Psychiatric Rating Scale (BPRS) has not been firmly established for panic disorder.  

     In a focused attempt to address the inadequacies of existing measures for panic outcome, researchers (95) have recently developed the Panic Disorder Severity Scale (PDSS). Modelled after the  Yale Brown Obsessive Compulsive Scale, the PDSS is a seven item interview based scale for assessment of panic disorder severity, specifically keyed to DSM1V criteria for panic disorder. Unlike previous instruments, the PDSS uniquely allows for a quick assessment of the severity of individual panic symptoms.  The scale was found to have both concurrent and discriminant validity , although the internal consistency of the instrument needs further study.  The PDSS may prove to be a valuable tool for assessing symptom severity and clinical improvement in both research and clinical settings studying panic disorder.

 

An Approach to Treatment Resistance

     Several factors must be considered when a panic disorder patient proves refractory to treatment.  First, it is essential for the clinician to confirm the accuracy of the diagnosis. Most commonly,  another anxiety disorder has been overlooked; in disorders such as social phobia and posttraumatic stress disorder, the occurrence of situationally bound panic attacks and avoidance behavior may mimic the symptoms of panic disorder in the natural environment. Abuse of illicit substances must be ruled out as intoxication or withdrawal states often present with panic attacks.  Treatment nonresponse may also be engendered by the presence of cormorbid psychiatric diagnoses. Specifically, major depressive disorder, substance use disorders, and other anxiety disorders are commonly associated with panic disorder and can confound pharmacological management.  Patients with the additional diagnosis of a personality disorder may prove problematic secondary to increased chronicity of symptomatology. Clearly, comorbid conditions need to be addressed both pharmacologically and psychotherapeutically to prevent stalling of treatment progress .

     When difficulties with established treatments are encountered, a full medical work up may be necessary to rule out a general medical condition that could be provoking panic. Temporal lobe epilepsy, chronic obstructive pulmonary disease, hyperthyroidism, and mitral valve prolapse are treatable disorders that entail panic symptoms as a significant part of their clinical presentation. In addition, concomitant medication use for separate conditions  may be exacerbating the underlying anxiety, warranting  inquiry into all current and past medications.

     If the diagnosis of panic disorder is accurate, it must be ensured that the pharmacological  treatment has been adequately administered.  A common mistake is to prematurely label a patient as treatment resistant without attempting to medicate at a sufficient or therapeutic dose. Despite an adequate dose, however,  the length of treatment necessary before therapeutic effect can be established is often underestimated, particularly with antidepressant pharmacotherapy.  Therapeutic effect generally emerges with at minimum 6-8weeks of treatment, although up to 12 weeks on a given agent may be necessary before response can be seen.  Treatment nonresponse may also be secondary to the patient’s noncompliance with the prescribed medication regimen. Heightened sensitivity to unwanted side effects is an important factor negatively affecting compliance, as is  lack of understanding of panic disorder as an illness that requires treatment. Medication intolerance needs to be managed by careful delineation of and attention to the specific side effects that are troublesome  and providing options for treatment. Hygenic measures for anxiety reduction, such as decreasing intake of caffeine and promoting adequate sleep, should be employed.

     Pharmacological management of treatment nonresponse is inherently flexible and entirely dependent on the clinical situation unique to each patient. However, it would be helpful to have available a pharmacological paradigm upon which treatment decisions can be based. The following provides a general strategy for the pharmacotherapy of treatment resistant panic.

     For patients on an initial agent such as a  SSRI or TCA and experiencing partial or no response, a high or low to mid potency benzodiazepine (alprazolam or lorazepam) should be added.  If this is unsuccessful, switching classes of the primary antidepressant ( while maintaining the benzodiazepine)  is the next step. For example, a patient not improving on fluoxetine may be switched to imipramine; alternatively, venlafaxine or nefazodone could be used.  To promote expediency, usually only one medication from each class should be tried. This strategy follows an underlying principle of antidepressant monotherapy  with judicious use of benzodiazepines.

     Depending on the situation, the clinician may choose to abandon monotherapy sooner rather than later.  If the reasonable possibilities for monotherapy have been exhausted and augmentation with benzodiazepines has been attempted, combination antidepressant therapy is the next consideration in the treatment strategy.  Addition of a TCA to an ongoing SSRI treatment has been demonstrated as beneficial (89).  The combination of a TCA and SSRI requires vigilance regarding tricyclic blood levels; the SSRIs ability to inhibit metabolism via cytochrome P450 will necessitate lower TCA doses. As with antidepressant monotherapy, the SSRI TCA combination may benefit from addition of a benzodiazepine if partial or no response is seen.

     If the above medications and combinations are unsuccessful, MAOIs can be utilized as an alternative. Although combination therapy with MAOIs and other antidepressants have been employed for major depressive disorder, this strategy is not recommended for panic patients.  Benzodiazepines, however, can be safely introduced to ongoing MAOI therapy.  The major difficulty with adding benzodiazepines to MAOIs is possible  precipitation of cognitive dulling.  Given the adverse side effect profile and the risk for hypertensive crisis, (and assuming no past or family history of good response to MAOI for the patient in question),  MAOIs should be the last class tried for antidepressant monotherapy.  RIMAs, a safer alternative, are currently unavailable in the United States.

     Refractoriness that persists despite the aforementioned treatments can be approached with additional augmentation strategies.  Lithium may be a viable option, particularly in patients with a personal or family history of mood disorders. Buspirone, though ineffective as the sole antipanic agent, can be added to an existing regimen to ameliorate generalized or anticipatory anxiety. The serotonergic properties of buspirone may also enhance the neurobiological action of more powerful antipanic drugs.  Patients with significant cardiovascular symptoms such as palpitations and tachycardia may derive benefit from beta-adrenergic antagonists (eg. propanolol, inderal) as  adjuntive therapy. When dizziness, lightheadedness and paresthesias are prominent in the clinical picture, additional treatment with a calcium channel blocker may target these symptoms and contribute to overall improvement.  In addition,  anticonvulsants such as valproate and gabapentin may be added to antidepressants for increased efficacy.

 

Neurocircuitry of Panic Disorder

     Knowledge regarding putative neurocircuits in panic disorder has become increasingly sophisticated. Over the past three decades, panic research has predominantly extrapolated from challenge studies and pharmacotherapy responses to elucidate complex interrelationships among serotonin, norepinephrine and gaba neurotransmitter systems.  These lines of research have been invaluable in defining potential mechanisms of action of antipanic drugs, as well as illuminating the  underlying pathophysiology of the illness. The most current understanding of brain mechanisms in panic disorder, however, has been additionally informed by advances in the basic neuroscience of anxiety and fear.

     Compelling work by scientists like Michael Davis of Emory University and Joseph Ledoux of New York University proved to be a watershed in the evolving delineation of anxiety neurocircuitry.  Their elegant experiments in rodents have outlined an elaborate neural network subserving the acquistion and maintenance of conditioned fear. Of critical significance to this model is the role of the amygdala. The amygdala, particularly the central nucleus (CNA), is uniquely situated to coordinate the physiological and behavioral  output observed in severe anxiety states (97,98).

    The amygdala recieves input from numerous areas that may serve to signal anxiety. Sensory stimuli and elemental danger cues are readily relayed from the sensory thalamus and brainstem structures to the central nucleus.  In response, efferents from the CNA project to diverse areas to produce the several physiological and behavioral components of the anxiety response: to the parabrachial nucleus producing an increase in respiratory rate (99) ; to the lateral hypothalamus activating the sympathetic nervous system and causing autonomic arousal and sympathetic discharge (100) ; to the locus ceruleus resulting in an increase in norepinephrine release, thereby increasing blood pressure and heart rate and behavioral fear responses (101) ; and to the paraventricular nucleus of the hypothalamus causing an increase in the release of adrenocorticoids (102). These responses bear striking resemblance to the manifestations of the clinical spontaneous panic attack.  Further projections to the periaqueductal grey (PAG) region lead to elicitation of defensive behaviors and freezing that may be analagous to phobic avoidance in humans (103).

     The amygdala has important reciprocal connections, not only with the aforementioned areas, but also with cortical regions that are involved in the processing and evaluating of sensory information (104). It is plausible that a neurocognitive deficit in these cortical processing pathways could result in the misinterpretation of bodily cues, or sensory stimuli, a prominent characteristic of panic disorder patients. A misread at this level could then lead to activation of the fear network through excessive excitatory input to the amygdala. Conversely, cognitive behavior therapy, a highly effective treatment for panic, could possibly buffer highly sensitive cortical areas to the effects of bodily stimulation.

     Potential effects of antipanic medications on the fear network are only beginning to be understood. SSRIs are particularly accessible in this regard, due to their comparatively circumscribed mechanism of action and their status as first line antipanic agents. Serotonergic neurons originate in the brainstem raphe region and have diffuse projections in the central nervous system (105). Three projections are of key relevance. First, serotonergic neurons have extensive inhibitory connections with the noradrenergic locus ceruleus. A net increase in serotonergic neurotransmission could decrease noradrenergic overactivity, a dominant aspect of  anxiety pathophysiology. This inhibition may attenuate several symptoms of sympathetic overdrive seen  in panic, such as tachycardia and increased blood pressure (106). Second, the raphe neurons project to the periaqueductal gray (PAG). Serotonin increase will decrease PAG activity, thereby attenuating defensive and escape behaviors (107). Third, SSRIs may, over long term treatment, decrease the release of corticotropin releasing factor from the hypthalamus (108). CRF controls stress induced increases in adrenocorticoids, as well as acting independently as a neurotransmitter that provides excitatory input to the fear network (109).  Of further significance is the fact that serotonergic neurons from the median and raphe nuclei have direct projections to the CNA via the medial forebrain bundle. Interestingly, increasing serotonin transmission can inhibit the amygdala’s response to excitatory input, particularly glutamatergic,from thalamic and cortical areas (105).

 

Conclusion

     Panic disorder is profoundly responsive to pharmacological intervention.  The emergence of increasingly safe and efficacious medications demands that all physicians develop a concise pharmacotherapeutic approach when treating these patients.  Although the relative success of existing medications has brought panic to the forefront of psychiatric research, specific areas require stronger focus.  The need for more double blind, placebo controlled trials cannot be overemphasized.  Further, the evaluation of medications over long term treatment needs to be significantly expanded.  Clinicians should also reinforce the psychoeducation of patients and families to promote greater understanding of the illness.